Transdermal hormone delivery system: compositions and methods

ABSTRACT

A transdermal hormone delivery system (THDS) is disclosed. The THDS is useful for control of fertility and as therapy for a variety of diseases and conditions treatable by robust delivery of progestin and estrogen hormones, particularly the progestin, levonorgestrel. The THDS comprises a backing layer, an adjoining adhesive polymer matrix comprising an effective amount of at least a progestin hormone, delivery of which is enhanced by one or more skin permeation enhancing agents present in pre-determined amounts. The THDS is capable of providing effective daily doses of progestin and estrogen hormones from a small surface area in contact with the skin, e.g., less than 20 square centimeters. Methods of fertility control and various types of hormone replacement therapy utilizing the THDS are also disclosed.

This application is a continuation-in-part of U.S. application Ser. No.10/130,913, filed May 23, 2002, which is a U.S. National Application ofInternational Application No. PCT/US00/32043, filed Nov. 22, 2000, whichclaims benefit of U.S. Provisional Application 60/167,535, filed Nov.24, 1999, the entire contents of each of which are incorporated byreference herein.

FIELD OF THE INVENTION

The present invention relates to hormone treatment for control offertility and as therapy for a variety of diseases and conditions.Specifically, the invention provides formulations and methods of use inconnection with a transdermal hormone delivery system for robustdelivery of steroid hormones.

BACKGROUND OF THE INVENTION

Various scientific articles and patent publications are referencedherein to describe the state of the art to which this inventionpertains. Each of these publications is incorporated by reference hereinin its entirety.

Hormone therapy using synthetic estrogens and/or progestins is currentlyused to control fertility and for treatment or prevention of a varietyof hormone-related conditions or deficiencies, including control ofacne, treatment of endometriosis, induction or prevention of amenorrhea,supporting pregnancy and treatment of galactorrhea, among numerousothers. Traditionally, combinations of synthetic estrogen and syntheticprogestin have been used in the past in orally administered dosageforms. Though the combination of synthetic progestin and estrogeneffectively suppresses ovulation, certain undesirable side effects areassociated with this type of oral contraceptive. For instance, theincidence of thromboembolic and related vascular disorders, includingstroke and myocardial infarction, is higher in women using oralcontraceptives; the relative risk may be eleven times greater in usersas compared to a control population. Further, the risk increases sharplyin women over 35 years of age. Contraceptive use has also beenassociated with increased evidence of benign liver tumors and anincreased risk of gallbladder disease. Additionally, fetal abnormalitiesmay result if a woman continues to take the pill after becomingpregnant.

Transdermal hormone delivery offers many advantages and avoids certaindisadvantages associated with oral contraceptives and hormonetreatments. Specifically, transdermal rate-controlled drugadministration avoids the variability in absorption and metabolismassociated with oral therapy. It further provides continuity of drugadministration, permitting the use of a pharmacologically active agentwith short biological half-life. Moreover, there is less chance of over-or under-dosing on a transdermal regimen, and patient compliance with amulti-day easy-to-use transdermal regimen is superior to daily oraldosing.

It is, therefore, highly desirable to provide formulations andtransdermal systems that permit 1) use of high levels of progestin, 2)use of either synthetic or natural estrogen, 3) use of a minimum numberof dosage units for each menstrual cycle, and further that provideappropriate levels of progestin and estrogen hormones to fully ensurefertility control or other treatment goals with minimal or no productionof undesired metabolic or chemical degradative products.

In recent years various transdermal contraceptive delivery systems forfertility control in females have been developed. U.S. Pat. No.5,296,230 describes a transdermal fertility controlling polymer matrixdosage unit comprising a backing layer, a polymer layer adhered to thebacking layer comprising microdispersed dosage amounts of estrogen andprogestin hormones, and an adhesive layer. U.S. Pat. No. 5,560,922discloses the delivery of a natural estrogen, 17β-estradiol, or ethinylestradiol or a combination thereof with an amount of naturalprogesterone or a progestin in a dosage unit comprising a backing layerand an adjoining polyacrylate adhesive polymer layer containingmicroreservoirs that release the hormones.

U.S. Pat. No. 5,788,983 discloses a transdermal polymer dosage unit, abacking layer and a reservoir layer, the reservoir layer having multipleregions that contact the skin during use and optionally containdifference pharmaceutical therapeutic agents providing a variable rateof absorption. U.S. Pat. No. 5,762,956 describes a transdermalcontraceptive delivery device and a method of fertility controlutilizing the device. The system comprises a backing layer, and anadhesive polymer matrix, which has dispersed therein hormones effectivefor controlling fertility, as well as a combination of three skinpermeation enhancers at a specified relative weight ratio.

The above described transdermal delivery systems are deficient in theirability to deliver sufficient quantities of progestin, particularlylevonorgestrel, either alone or in proper balance with a selectedestrogen, for one or more of a variety of reasons. For instance, thesystems described in U.S. Pat. No. 5,296,230, U.S. Pat. No. 5,560,922and U.S. Pat. No. 5,788,983 comprise dosage units that are cumbersome insize, e.g., with surface area up to 100 cm². The dosage unit describedin U.S. Pat. No. 5,762,956 is purportedly smaller, but the amount ofprogestin delivered is not robust.

Accordingly, there is a need in the art for a transdermal hormonedelivery system, and drug-delivery formulations for use therein, thatcan reliably achieve high serum levels of hard-to-deliver progestins,such as levonorgestrel, and a desired profile of progestin and selectedestrogen for contraception and other purposes, with minimal sideeffects. It is also desirable that the dosage unit is comfortably-sized,cosmetically unobtrusive and reliably adherent.

SUMMARY OF THE INVENTION

The present invention is directed to a skin permeation enhancercomposition for enhancing the absorption through the skin of a steroidhormone, to hormone delivery formulations, to a transdermal hormonedelivery system (THDS) comprising a backing layer and an adhesivepolymer matrix which has dispersed therein at least one hormoneeffective for controlling fertility or for other hormone therapy, and torelated compositions and methods. The hormone delivery formulation,which can be utilized in the adhesive polymer matrix of the THDS,comprises one or more skin permeation enhancers, as specified in detailherein, a humectant/plasticizer and a polymer. The relative and absoluteamounts of the respective skin permeation enhancers in the THDS areadjusted for optimum hormone delivery by utilizing specified amounts ofstarting materials and by controlling process parameters for producingthe THDS, such as drying time and temperature.

According to one aspect of the invention, a skin permeation enhancercomposition is provided for use in fabricating a transdermal hormonedelivery system for delivery of one or more of a progestin, estrogen ortestosterone hormone. The composition comprises a combination of apharmaceutically acceptable organic solvent (e.g., dimethyl sulfoxide),a fatty (C₈-C₂₀) alcohol ester of a hydroxy acid (e.g., lactic acid), alower (C₁-C₄)alkyl ester of a hydroxy acid (e.g., lactic acid), and aC₆-C₁₈ saturated or unsaturated fatty acid, such as capric acid. In apreferred embodiment utilizing DMSO, a fatty alcohol ester of lacticacid, a lower alkyl ester of lactic acid and capric acid, the fourexcipients are combined in a weight ratio of 2:1:1:0.8 to 6:1:1:0.8,respectively, more specifically, 3:1:1:0.8 to 4:1:1:0.8, respectively.In specific embodiments, the fatty alcohol ester of lactic acid islauryl lactate and the lower alkyl ester of lactic acid is ethyllactate.

Another aspect of the invention features a polymer formulation for usein fabricating a transdermal hormone delivery system of a typecomprising a backing layer and a polymer matrix, preferably an adhesivepolymer matrix, in which is dispersed one or more of a progestin,estrogen or testosterone hormone to be transdermally delivered. Thisformulation comprises a polymer and, on a weight percentage basis, fromabout 0% to about 5% humectant/plasticizer, and from about 10% to about30% of a skin permeation enhancer composition comprising a combinationof a pharmaceutically acceptable organic solvent (e.g., dimethylsulfoxide), a fatty (C₈-C₂₀) alcohol ester of a hydroxy acid (e.g.,lactic acid), a lower (C₁-C₄)alkyl ester of a hydroxy acid (e.g., lacticacid), and a C₆-C₁₈ saturated or unsaturated fatty acid, such as capricacid. In a preferred embodiment utilizing DMSO, a fatty alcohol ester oflactic acid, a lower alkyl ester of lactic acid and capric acid, thefour excipients are combined in a weight ratio of 2:1:1:0.8 to6:1:1:0.8, respectively, more specifically, 3:1:1:0.8 to 4:1:1:0.8,respectively. Preferably the polymer is an adhesive polymer and, incertain embodiments, the adhesive polymer is a polyacrylate adhesivecopolymer. More specifically, the polyacrylate adhesive copolymercomprises a 2-ethylhexyl acrylate monomer and further comprises about 3%to about 60% w/w vinyl acetate. In certain embodiments, thehumectant/plasticizer is a polyvinylpyrrolidone/vinyl acetate. Incertain embodiments, the fatty alcohol ester of lactic acid is lauryllactate and the lower alkyl ester of lactic acid is ethyl lactate.

In certain embodiments of the invention, the polymer formulationcomprises a progestin, which is levonorgestrel in preferred embodiments.The polymer formulation also may comprise a progestin and an estrogen,specifically levonorgestrel and ethinyl estradiol or 17β-estradiol. Anexemplary embodiment of this type of formulation comprises, on a weightpercentage basis, about 79.65% polyacrylate adhesive copolymer, about1.25% polyvinylpyrrolidone/vinyl acetate, about 9.51% dimethylsulfoxide, about 3.10% lauryl lactate, about 3.10% ethyl lactate, about2.39% capric acid, about 0.58% levonorgestrel and about 0.28% ethinylestradiol. In other embodiments, the polymer formulation comprises aprogestin, and estrogen and a testosterone. In yet other embodiments,the formulation comprises a testosterone alone.

Another aspect of the invention features a THDS comprising a backinglayer that is substantially impermeable to skin permeation enhancingagents, and progestin and estrogen hormones to be deliveredtransdermally. The hormones are dispersed in an adhesive polymer matrixaffixed to the backing layer. The adhesive polymer matrix is made fromthe adhesive polymer formulation described above. After fabrication ofthe THDS is complete, the adhesive polymer matrix comprises, on a finalweight percentage basis of the adhesive polymer matrix: from about 0% toabout 5% of a humectant/plasticizer; from about 12% to about 36% percentof a combination of skin permeation enhancing agents which is a mixturecomprising from about 4% to about 12% of an pharmaceutically acceptableorganic solvent, such as dimethyl sulfoxide, from about 4.2% to about12.6% fatty (C₈-C₂₀) alcohol ester of hydroxy acid (e.g., lactic acid),from about 0.7% to about 2.3% lower (C₁-C₄)alkyl ester of hydroxy acid(e.g., lactic acid), and from about 3% to about 9% C₆-C₁₈ fatty acid,such as capric acid; and an amount of one or more of the respectivehormones effective to provide a pre-determined daily dose of eachhormone for between about one and about nine days. In certainembodiments, the progestin is levonorgestrel and the estrogen is ethinylestradiol or 17β-estradiol. Alternative embodiments comprise adaptationof the THDS for delivery of (1) a progestin alone, (2) a testosterone inaddition to the progestin and the estrogen, or (3) a testosterone alone.

In specific embodiments of the invention, the humectant/plasticizer is apolyvinylpyrrolidone/vinyl acetate. The adhesive copolymer comprises apolyacrylate copolymer, preferably one that comprises a 2-ethylhexylacrylate monomer and further contains about 3 to 60% w/w vinyl acetate.

In addition to the specified amounts of skin permeation enhancers setforth above in the post-fabrication THDS, certain embodiments call forthe enhancers to be present in a weight ratio of about 4-8 parts DMSO,about 4-8 parts fatty alcohol ester of lactic acid, about 1 part loweralkyl ester of lactic acid and about 3-6 parts capric acid. It ispreferred that the DMSO and the fatty alcohol ester of lactic acid arepresent in a weight ratio of between about 1.5:1 and about 1:1.5.

In specific embodiments, the THDS is formulated for delivery of ethinylestradiol and levonorgestrel, wherein the ethinyl estradiol istransdermally delivered at a rate of between about 10 μg and 50 μg perday for a term of about one day to about nine days, and thelevonorgestrel is transdermally delivered at a rate of at least 20 μgper day, more specifically at least 30 μg per day, for a term of aboutone day to about nine days. In use, the THDS transdermally deliverssufficient levonorgestrel to produce a steady state serum concentrationof at least 1,000 pg/ml.

A THDS of the invention is capable of robust delivery of progestin,estrogen and testosterone hormones, even from a comparatively smallsurface area. Accordingly, another aspect of the invention features aTHDS comprising a backing layer and an adhesive polymer matrix, whereinthe adhesive polymer matrix is of a maximum surface dimension of about20 cm² and a maximum cross-sectional dimension of about 300 μm and iscapable of delivering at least 20 μg/day, more preferably at least 30μg/day, levonorgestrel for between about one and about nine days. Inpreferred embodiments the adhesive polymer matrix is of a maximumsurface dimension of 17.5 cm² or 15 cm². In specific embodiments, theTHDS is formulated for delivery of levonorgestrel and delivers an amountof levonorgestrel sufficient to impart a serum concentration oflevonorgestrel of at least 1,000 pg/ml.

In other embodiments, the THDS is formulated for delivery oflevonorgestrel and an estrogen, such as ethinyl estradiol or17β-estradiol. More specifically, the estrogen is ethinyl estradiol andis transdermally delivered at between 10 μg and 50 μg per day forbetween about 1 and about nine days.

The THDS of the invention is made by combining appropriate amounts ofadhesive polymer, humectant/plasticizer, skin permeation enhancingagents and hormones, then coating the mixture onto the backing layer anddrying the coated mixture at a pre-determined temperature for apre-determined time. In an alternative embodiment, the adhesive polymerformulation is coated onto a piece of release liner. Starting amounts ofingredients and process parameters (e.g., coating thickness and dryingtime and temperature) are adjusted to arrive at the final weight ratiosand weight percents of the respective skin permeation enhancing agents.Specifically, the method comprises: (1) preparing an adhesive polymerformulation by combining an adhesive copolymer solution with, on aweight percentage basis of the adhesive polymer formulation: from about0% to about 5% of a humectant/plasticizer; from about 10% to about 30%percent of a combination of skin permeation enhancing agents which is amixture comprising a pharmaceutically acceptable organic solvent, suchas DMSO, a fatty (C₈-C₂₀) alcohol ester of a hydroxyl acid, such aslactic acid, a lower (C₁-C₄)alkyl ester of a hydroxyl acid, such aslactic acid, and a C₆-C₁₈ fatty acid, such as capric acid; and an amountof one or more of the selected hormones effective to provide apre-determined daily dose of each hormone for between about one andabout nine days, thereby forming an adhesive polymer matrix startingsolution; (2) coating the adhesive polymer starting solution onto thebacking layer; and (3) drying the coated backing layer for a time and ata temperature sufficient to produce a transdermal hormone deliverysystem as described above. In specific embodiments, the adhesive polymerstarting formulation is coated onto the backing layer at a thickness ofbetween about 300 μm and about 800 μm, the coated material dried forbetween about 5 minutes and about 25 minutes at a temperature betweenabout 40° C. and about 80° C.

In certain embodiments, the THDS dosage unit is supplied with an overlaylayer. The overlay layer may be affixed to the backing layer or it maybe supplied separately, for application at the user's discretion. Theoverlay layer is coated with an adhesive and extends beyond theperimeter of part or all of the backing layer and adhesive polymermatrix. In an alternative embodiment, a non-adhesive polymer issubstituted for the adhesive polymer, and skin adhesion is effected bythe adhesive present in the overlay.

According to another aspect of the invention, a method of controllingfertility is provided, which comprises applying to the skin of a subjectdesiring such treatment a THDS as described above. The THDS is replacedonce each week for three of four successive weeks of a menstrual cycle,for successive menstrual cycles extending as fertility control isdesired. In specific embodiments, the THDS delivers levonorgestrel andan estrogen, preferably ethinyl estradiol or 17β-estradiol. In otherembodiments, the THDS is adapted for delivery of a progestin alone,preferably levonorgestrel.

In preferred embodiments, the method comprises transdermal delivery ofethinyl estradiol and levonorgestrel, wherein the ethinyl estradiol isdelivered at a rate of between about 10 μg and 50 μg per day for a termof about one day to about nine days, and the levonorgestrel is deliveredat a rate of at least 20 μg per day, preferably at least 30 μg per day,for a term of about one day to about nine days. In these embodiments ofthe method, the levonorgestrel is delivered in an amount sufficient toproduce a blood concentration of at least 1,000 pg/ml, which exceedsrequired fertility-controlling serum levels.

The foregoing method is adaptable for individuals wishing to eliminatemenses entirely. In this instance, the THDS is replaced once each weekfor consecutive weeks extending as fertility control and elimination ofmenses is desired.

In another adaptation, the THDS of the invention is formulated fordelivery of testosterone alone. The THDS is used for treatment ofdeficiencies of circulating testosterone levels, resulting in decreasedlibido (both male and female), with the treatment comprising applying aTHDS once each week for consecutive weeks extending as long as thetreatment is desired.

Other features and advantages of the invention will be understood byreference to the detailed description and examples that follow.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

Set forth below are various embodiments of the invention, includingformulations used to make the adhesive polymer matrix of the THDSdescribed herein, as well as process parameters for fabricating the THDSsuch that it can reliably achieve high serum levels of hard-to-deliverprogestins, such as levonorgestrel, and a desired profile of progestinand selected estrogens and/or other hormones, for contraception andother purposes. These formulations and the THDS produced using theseformulations differ from those currently disclosed or available, andconstitute a significant advance in the art of transdermal hormonedelivery. In one aspect, a THDS of the present invention comprises aprogestin, most suitably levonorgestrel, and an estrogen, most suitablyethinyl estradiol or 17-β estradiol, dispersed in an adhesive polymermatrix affixed to a backing layer. In another aspect, the THDS comprisesonly a progestin. In other aspects, the THDS comprises a progestin, anestrogen and a testosterone, or a testosterone alone.

Dosage units of the THDS of the invention, sometimes referred to hereinas “patches,” in their most simple form comprise a backing layer towhich is affixed an adhesive polymer matrix containing the hormones tobe delivered and other excipients that facilitate the appropriate rateof transdermal delivery of those hormones. Briefly, the dosage units aremade by combining the adhesive polymer, hormones and excipients into astarting formulation, coating that formulation onto the backing layer(or onto a release liner in an alternative embodiment), and drying thecoated backing layer for a specific time, at a specific temperature,which is designed to produce a dosage unit in which the hormones andexcipients are present in specific amounts that are optimum for thedelivery of the hormones. For reasons described in detail herein, theamounts of respective components within the starting formulation aredifferent from the amounts of components found in the final THDS afterthe fabrication process is complete. To distinguish these, the terms“adhesive polymer formulation,” “adhesive polymer solution” or “startingsolution” are used herein to refer to the starting formulation, prior tocoating onto the backing layer and drying. The term “adhesive polymermatrix” is used herein to refer to the adhesive polymer solution afterit has been coated onto the backing layer and dried (i.e.,“post-fabrication”).

Components of the Adhesive Polymer Formulation:

Skin Permeation Enhancers:

Drug molecules released from a transdermal delivery system must becapable of penetrating each layer of skin. In order to increase the rateof permeation of drug molecules, a transdermal drug delivery system mustbe able in particular to increase the permeability of the outermostlayer of skin, the stratum corneum, which provides the most resistanceto the penetration of molecules. In this regard, the present inventionprovides a transdermal hormone delivery system that employs one or moreskin permeation enhancers in specific amounts. It is the control ofabsolute and relative amounts of skin permeation enhancers that providesthe sufficient flux of the penetrating hormones. The skin permeationenhancers also provide the desired permeation rate ratio of thesehormones to achieve the desired amounts to be released from thetransdermal contraceptive delivery system and delivered into the body toproduce the desired effect.

A combination of skin permeation enhancing agents is preferably employedin the practice of the present invention. The combination comprises amixture of (1) a pharmaceutically acceptable organic solvent, such asdimethyl sulfoxide (DMSO), (2) a fatty (C₈-C₂₀) alcohol ester of ahydroxy acid, such as lauryl lactate, (3) a lower (C₁-C₄)alkyl ester ofa hydroxy acid, e.g., ethyl lactate, and (4) a C₆-C₁₈ fatty acid, suchas capric acid. For optimum hormone delivery, these skin permeationenhancers are present at specified amounts within the adhesive polymermatrix, as set forth in detail below. In certain embodiments, one ormore of the skin permeation enhancers may be eliminated from the polymermatrix. However the specific amounts of the remaining enhancers andtheir relative ratios in weight percent (in both the starting solutionand the final dosage unit) should remain within the ranges set forthherein.

In a preferred embodiment, the pharmaceutically acceptable organicsolvent is DMSO. Other organic solvents suitable for use in the presentinvention include, but are not limited to, C₁-C₈ branched or unbranchedalcohols, such as ethanol, propanol, isopropanol, butanol, isobutanol,and the like, as well as azone (laurocapram:1-dodecylhexahydro-2H-azepin-2-one) and methylsulfonylmethane, to name afew.

The fatty alcohol ester of hydroxy acid preferably is a fatty alcoholester of lactic acid, such as lauryl lactate. However, other hydroxyacids and fatty alcohols may be utilized. Alternative hydroxy acidsinclude, but are not limited to, alpha-hydroxy acids such as glycolicacid, tartaric acid, citric acid, malic acid and mandelic acid, as wellas the beta-hydroxy acid, salicylic acid. Alternative fatty alcoholsinclude any C₈-C₂₀ saturated or unsaturated fatty alcohol, such asmyristyl, palmityl or oleyl alcohols, to name a few.

The lower alkyl ester of hydroxy acid also preferably utilizes lacticacid, and most preferably is ethyl lactate. However, other hydroxyacids, such as glycolic acid, tartaric acid, citric acid, malic acid,mandelic acid and salicylic acid, may also be utilized. In additionisopropylmyristic acid (IPM) may be used as a substitute for the loweralkyl ester of hydroxy acid.

The inventor has discovered that inclusion of a medium- to long-chainfatty acid in the skin permeation enhancer formulation improves thetransdermal delivery profile of the hormones utilized in the presentinvention. Capric acid is preferred for use. However, other C₆-C₁₈saturated or unsaturated fatty acids may be used, including but notlimited to caproic acid, caprytic acid, lauric acid and myristic acid,to name a few.

The aforementioned combination of skin permeation enhancers may be usedto enhance transdermal delivery of steroid hormones from any type oftransdermal delivery device. An adhesive polymer matrix-type system asdescribed in detail herein is preferred for use; however, the enhancercombination may also be utilized in non-adhesive polymers, as well as inmulti-layer or reservoir-type transdermal delivery systems, to name afew.

Hormones:

A THDS utilizing the aforementioned skin permeation enhancers can beused to deliver any type of hormone capable of transdermal delivery.More specifically, a THDS of the invention is formulated for delivery ofanimal steroid hormones. In one embodiment, a combination of a progestinand an estrogen is utilized for one or more of the following purposes:(1) control of fertility, (2) control of acne, (3) treatment ofendometriosis, and (4) induction of amennorhea. In another embodiment, aprogestin alone is utilized for one or more of the following purposes:(1) control of fertility, (2) supporting pregnancy, (3) as analternative hormonal therapy for individuals for whom estrogen iscontra-indicated (e.g., lactating females), and (4) preventinggalactorrhea. In still another embodiment, a combination of progestin,estrogen and testosterone is utilized as a hormone replacement therapyfor the treatment of deficiency of these hormones in females. Yetanother embodiment is directed to a THDS formulated for delivery oftestosterone alone, which is useful for the treatment of decreasedlibido resulting from testosterone deficiency in both males and females.

A THDS of the invention comprising levonorgestrel is preferred for bothcombination hormone delivery and progestin-alone delivery.Levonorgestrel is known to be recalcitrant to transdermal delivery;however, the hormone is effectively delivered from the THDS of thepresent invention. With the controlled release of the hormone at arelatively steady rate over a prolonged period, typically several daysand preferably one week to nine days, the subject is provided with thebenefit of a steady infusion of hormones over a prolonged period.

Levonorgestrel is a potent progestin on a weight-dose basis, which is animportant factor since the progestins often exhibit a much lesser degreeof transdermal absorption than do the estrogens. Other progestins thatcould be used in part or total are norgestrel, norgestimate,desogestrel, gestodene, norethindrone, norethynodrel, hydrogesterone,ethynodiol dicetate, hydroxyprogesterone caproate, medroxyprogesteroneacetate, norethindrone acetate, progesterone, megestrol acetate,gestogen and certain others which are biocompatible and absorbabletransdermally. These include biocompatible derivatives of progestinsthat are transdermally absorbed, some of which, advantageously, arebioconvertible after transdermal absorption to the original progestin.The progestin and other hormones selected should have high compatibilitywith each other.

For combinations of progestin with estrogen, the synthetic hormoneethinyl estradiol is particularly suitable. This hormone may betransdermally delivered in conjunction with the particularly suitableprogestin, levonorgestrel, by a TDHS of the present invention atdesirable daily rates for both hormones. Ethinyl estradiol andlevonorgestrel are compatible and can be dispersed in the adhesivepolymer formulation. Typically, a transdermal dosage unit designed forone-week therapy should deliver at least about 20 μg/day oflevonorgestrel (or an equivalent effective amount of another progestin)and 10-50 μg/day of ethinyl estradiol (or an equivalent effective amountof another estrogen). Those respective amounts of progestin and estrogenare believed to be necessary to inhibit ovulation and to maintain normalfemale physiology and characteristics. In the present invention, theamount of levonorgestrel transdermally delivered is preferably 30 μg perday for more than one day to about one week with a 15 cm² transdermaldelivery device.

Derivatives of 17β-estradiol that are biocompatible, capable of beingabsorbed transdermally and preferably bioconvertible to 17β-estradiolmay also be used, if the amount of absorption meets the required dailydose of the estrogen component and if the hormone components arecompatible. Such derivatives of estradiol include esters, either mono-or di-esters. The monoesters can be either 3- or 17-esters. Theestradiol esters can be, illustratively speaking,estradiol-3,17-diacetate; estradiol-3-acetate; estradiol 17-acetate;estradiol-3,17-divalerate; estradiol-3-valerate; estradiol-17-valerate;3-mono-, 17-mono- and 3,17-dipivilate esters; 3-mono-, 17-mono- and3,17-dipropionate esters; 3-mono-, 17-mono- and 3,17-dicyclopentyl-propionate esters; corresponding cypionate, heptanoate, benzoateand the like esters; thinyl estradiol; estrone; and other estrogenicsteroids and derivative thereof that are transdermally absorbable.

Combinations of the above with estradiol itself (for example, acombination of estradiol and estradiol-17-valerate or further acombination of estradiol-17-valerate and estradiol-3,17-divalerate) canbe used with beneficial results. For example, 15-80% of each compoundbased on the total weight of the estrogenic steroid component can beused to obtain the desired result. Other combinations can also be usedto obtain desired absorption and levels of 17β-estradiol in the body ofthe subject being treated.

Formulations comprising testosterone may utilize natural testosterone orsynthetic testosterones that are absorbed transdermally. For instance,methyl testosterone is suitable for use in the present invention. Inpremenopausal women, the rate of testosterone production is about 300μg/day. Accordingly, THDS for testosterone delivery should be formulatedfor deliver of an amount of testosterone to supplement a partial ortotal deficiency, i.e., up to about 300 μg daily. Likewise, fortreatment of testosterone deficiency in males, THDS should be formulatedto deliver up to about 3-6 mg daily.

It will be appreciated that the hormones may be employed not only in theform of the pure chemical compound, but also in admixture with otherpharmaceuticals that may be transdermally applied or with otheringredients which are not incompatible with the desired objective aslisted above. Thus, simple pharmacologically acceptable derivatives ofthe hormones such as ethers, esters, amides, acetals, salts and thelike, if appropriate, may be used. In some cases, such derivatives maybe preferred. The progestin compound and the estrogenic steroid areordinarily dispersed or dissolved concurrently in fabricating thehormone-containing adhesive polymer matrix or they may be dispersed ordissolved separately.

Adhesive Polymer:

Generally, polymers used to form the biologically acceptable adhesivepolymer matrix are those capable of forming thin films or coatingsthrough which hormones can pass at a controlled rate. Suitable polymersare biologically and pharmaceutically compatible, nonallergenic,insoluble in and compatible with body fluids or tissues with which thedevice is contacted. The use of soluble polymers is to be avoided sincedissolution or erosion of the matrix would affect the release rate ofthe hormones as well as the capability of the dosage unit to remain inplace for convenience of removal.

Suitable materials for the adhesive polymer formulation includepolyethylene, polypropylene, ethylene/propylene copolymers,ethylene/ethyl acrylate copolymers, ethylene/vinyl acetate copolymers,silicone elastomers, especially the medical-grade polydimethylsiloxanes,neoprene rubber, polyisobutylene, polyacrylates, chlorinatedpolyethylene, polyvinyl chloride, vinyl chloride-vinyl acetatecopolymer, crosslinked polymethacrylate polymers (hydro-gel),polyvinylidene chloride, poly(ethylene terephthalate), butyl rubber,epichlorohydrin rubbers, ethylenevinyl alcohol copolymers,ethylenevinyloxyethanol copolymers; silicone copolymers, for example,polysiloxanepolycarbonate copolymers, polysiloxanepolyethylene oxidecopolymers, polysiloxane-polymethacrylate copolymers,polysiloxane-alkylene copolymers (e.g., polysiloxane-ethylensilanecopolymers), and the like; cellulose polymers, for example methyl orethyl cellulose, hydroxypropyl methy cellulose, and cellulose esters;polycarbonates; polytetrafluoroethylene; and the like.

Preferably, the adhesive polymer should be selected from polymers withglass transition temperatures below room temperature. The polymer may,but need not necessarily, have a degree of crystallinity at roomtemperature. Cross-linking monomeric units or sites can be incorporatedinto such polymers. For example, cross-linking monomers that can beincorporated into polyacrylate polymers include polymethacrylic estersof polyols such as butylene diacrylate and dimethacrylate, trimethylolpropane trimethacrylate and the like. Other monomers that provide suchsites include allyl acrylate, allyl methacrylate, diallyl maleate andthe like.

Preferably, the adhesive polymer formulation comprises a polyacrylateadhesive polymer of the general formula (I):

wherein x represents the number of repeating units sufficient to providethe desired properties in the adhesive polymer and R is H or a lower(C₁-C₁₀)alkyl, such as ethyl, butyl, 2-ethylhexyl, octyl, decyl and thelike. More specifically, it is preferred that the adhesive polymermatrix comprises a polyacrylate adhesive copolymer having a 2-ethylhexylacrylate monomer and approximately 50-60% w/w of vinyl acetate as aco-monomer. An example of a suitable polyacrylate adhesive copolymer foruse in the present invention includes, but is not limited to, that soldunder the tradename of Duro Tak 87-4098 by National Starch and ChemicalCo., Bridgewater, N.J., which comprises a certain percentage of vinylacetate co-monomer.

Humectant/Plasticizer:

Preferably, a plasticizer/humectant is dispersed within the adhesivepolymer formulation. Incorporation of a humectant in the formulationallows the dosage unit to absorb moisture on the surface of skin whichin turn helps to reduce skin irritation and to prevent the adhesivepolymer matrix of the delivery system from failing. Theplasticizer/humectant may be a conventional plasticizer used in thepharmaceutical industry, for example, polyvinyl pyrrolidone (PVP). Inparticular, PVP/vinyl acetate co-polymers, such as those having amolecular weight of from about 50,000, are suitable for use in thepresent invention. The PVP/vinyl acetate acts as both a plasticizer,acting to control the rigidity of the polymer matrix, as well as ahumectant, acting to regulate moisture content of the matrix.Preferably, the PVP/vinyl acetate is PVP/VA S-630 supplied byInternational Specialty Products, Inc. (ISP) of Wayne, N.J., wherein thePVP and the vinyl acetate are each present in approximately equal weightpercent.

Backing Layer:

The backing layer can be made of any suitable material that isimpermeable to the hormones and other excipients of the adhesive polymermatrix. The backing layer serves as a protective cover for the matrixlayer and provides a support function. The backing layer can be formedso that it is essentially the same size as the hormone-containingadhesive polymer matrix or it can be of larger dimension so that it canextend beyond the sides of the adhesive polymer matrix outwardly so thatthe surface of the extension of the backing layer can be the base for anadhesive overlay, as described in greater detail below. The backinglayer can be any appropriate thickness that will provide the desiredprotective and support functions. A suitable thickness is from about 10to about 300 microns. More specifically, the thickness is less thanabout 150 microns, yet more specifically, it is less than about 100microns, and most specifically, the thickness is less than about 50microns.

Examples of materials suitable for making the backing layer are films ofhigh and low density polyethylene, polypropylene, polyurethane,polyvinylchloride, polyesters such as poly(ethylene phthalate), metalfoils, metal foil laminates of such suitable polymer films, and thelike. Polyester films, such as Scotchpak® 9732 (3M Company), areparticularly suitable for use in the present invention.

Preparation of Adhesive Polymer Formulation:

In accordance with the present invention, THDS dosage units are madewith attention to the concentration of ingredients within the patch atcompletion of the fabrication process. Accordingly, parameters that maybe varied to achieve the appropriate final amounts and ratios ofingredients include the starting formulation, as well as the processparameters utilized to fabricate the patch, as described below.

In making the hormone-containing adhesive polymer formulation,polyacrylate adhesive polymers of the formula described above arepreferably utilized. The hormones are added in an amount determined bythe hormone dosage and the duration of treatment desired in each dosageunit.

Generally speaking, it is preferred that the starting formulationcomprises between about 10 and about 30 percent of skin permeationenhancer combination based on the weight of the adhesive polymerstarting solution. More preferably, about 13 to 27%, yet more preferablyabout 16-24% or even more preferably, about 19-21% of skin permeationenhancer combination is used, based on the weight of the adhesivepolymer starting solution. In preferred embodiments, the skin permeationenhancers are formulated within the adhesive polymer starting solutionat a weight ratio (weight % of the adhesive polymer matrix) of:2:1:1:0.8 to 6:1:1:0.8, of DMSO, fatty alcohol ester of lactic acid,lower alkyl ester of lactic acid, and capric acid, respectively. Morespecifically, the ratio is 3:1:1:0.8 to 4:1:1:0.8. These weight ratiosare particularly suitable for THDS fabricated using process parameterscomprising coating the adhesive solution onto the backing layer at athickness between 500 μm and 700 μm and drying at about 60° C. for about15 minutes.

As can be seen from the data presented in Examples 1-3, differentialgains/losses of the various skin permeation enhancers occur during theprocess of fabricating the THDS. For instance, under the processparameters set forth in Examples 1-3, the weight percent of DMSO in thepost-fabrication adhesive polymer matrix is between about 65 and 90% ofthe amount added to the starting formulation. Likewise, ethyl lactatedecreases to about 50-75% of its initial amount. In contrast, the finalamount of lauryl lactate is about 2.6 to four-fold greater than thestarting percentage and capric acid similarly increases to about2.5-3.9-fold its initial starting percentages. These differentialchanges likely result from an overall decrease in volume of thepost-fabricated matrix, combined with differences in volatility of therespective skin permeation enhancers. Regardless of the underlyingreasons for the observed changes, the amounts of respective enhancers inthe starting formulation should take into account the differential gainsor losses that occur during processing. One of skill in the art would becapable of making the appropriate adjustments for starting materials,utilizing the information provided herein as well as informationcommonly available to pharmaceutical and medicinal chemists.

It is preferred that the hormone-containing adhesive polymer matrixcontains some excess of the dispersed hormone over the dosage amountdesired to be delivered. To accomplish this, the starting formulationcan comprise an excess of hormone of about 5.0 to about 50 times thedesired dosage. More preferably, the excess is about 10 to about 25times the desired dosage to be transdermally absorbed.

In THDSs formulated for delivery of an estrogen and a progestin, it ispreferred that the starting formulation comprise a ratio of progestin toestrogen of at least about 1.8:1, yet more preferably about 2:1. Whilenot intending to be bound by any particular mechanism of action, it isbelieved that the inclusion of a lesser amount of estrogen increases theamount of free progestin in the blood because estrogen is known toinduce the production of sex hormone binding globulin, which bindsprogestin. For this reason, not only is the ratio of progestin toestrogen believed to be significant, but also the total amount ofestrogen in the formulation preferably is kept to a minimum, e.g., lessthan about 0.3% by weight of the starting adhesive polymer formulationas described herein.

Depending upon the hormones utilized and the drug delivery desired, asuitable amount of a plasticizer can be varied from zero to about 10percent, based on the weight of the adhesive polymer matrix. Preferably,the amount of humectant/plasticizer present in the final dosage unit isless than 5%. When PVP/vinyl acetate is used, it can be added as anaqueous solution with the PVP/vinyl acetate content varying from 0.5 toabout 5 percent, based on the weight of the final dried matrix of thepatch, noting that the weight percent of the humectant/plasticizer isgreater in the final product as compared with the starting formulation.

Example 1 sets forth an exemplary starting formulation of the invention.This formulation is suitable for use with the preferred fabricationprocess parameters set forth below.

Preferably, prior to mixing with adhesive polymer, the hormones used aredissolved and dispersed in a solution comprising the plasticizer and thecombination of skin permeation enhancers. More preferably, the enhancercombination and the plasticizer solution are combined, the hormonesadded thereto and subjected to mixing.

Typically, the adhesive polymer solution is added to the solution ofhormones dispersed in the enhancer combination/plasticizer solution. Themixture of adhesive polymer and the plasticizer/enhancer/hormonesolution is then thoroughly mixed using a high-torque mixer to form ahomogeneous dispersion or solution of the hormones in the adhesivepolymer. The mixed solution is then allowed to stand undisturbed untildeaerated, e.g., for a time period of at least one hour up to 24 hours.

Fabrication of THDS Dosage Units:

Once deaerated, the adhesive polymer solution is applied to the backinglayer material, and subsequently dried for a set time at a settemperature. In an alternative embodiment, the adhesive polymer matrixmay be applied to a release liner instead of to the backing layer.Accordingly, reference herein to application of the adhesive polymermatrix to the backing layer will be understood to include thisalternative embodiment. Application of the deaerated adhesive polymermatrix to the backing layer may be accomplished using commerciallyavailable laboratory coating/drying apparatus routinely used for thispurpose. For instance, the Werner Mathis Model LTSV/LTH apparatus may beutilized, as well as other laboratory coating devices available fromWerner Mathis AG (Zurich, Switzerland). Other suitable devices include,but are not limited to, instruments produced by Cheminstruments, Inc.(Cincinnati, Ohio).

The thickness of the adhesive polymer solution applied to the backinglayer, as well as the time and temperature of drying, are all processparameters that can be varied to achieve the final concentrations andratios of hormones and permeation enhancing agents within the patch. Forinstance, as described in greater detail in Example 3, it has been foundthat a change in the thickness of adhesive polymer matrix applied to thebacking layer (e.g., from 300 to 800 μm) results in an overall greaterretention of skin permeation enhancers when the other two processparameters, drying time and drying temperature, are held constant. Incontrast, changing the drying time, e.g., from 5 to 25 minutes, or thedrying temperature, e.g., from 40-100° C., results in overall losses inretention of skin permeation enhancers, to a greater or lesser degreedepending on the enhancer.

Thus, it will be appreciated by those of skill in the art that, inaddition to selection of appropriate amounts of starting materials inthe adhesive polymer starting formulation, an appropriate combination of(1) initial thickness of the deaerated adhesive polymer solution spreadon the backing layer, (2) drying time and (3) drying temperature may beselected to achieve the final composition of skin permeation enhancersand hormones in the THDS, as set forth below. A suitable initialthickness of the deaerated adhesive polymer matrix can range from 300 to800 μm, more specifically from 400 or 500 to 700 μm, with an averagethickness being about 600-700 μm. A suitable drying time should be atleast five minutes, but can range to 10, 15, 20, 25 or more minutes,depending on the other process parameters chosen. Likewise, a suitabledrying temperature ranges from room temperature to 40, 50, 60, 70 or 80°C., again depending on the process parameters chosen. In preferredembodiments, the initial thickness of the coated solution is about500-700 μm, more preferably 600-700 μm; the drying temperatures is about50-80° C., more preferably 55-65° C., yet more preferably about 60° C.;and the drying time is about 10-20 minutes, more preferably about 15minutes. An exemplary embodiment of the invention utilizes an initialcoating thickness of 600-700 μm, a drying temperature of 60° C. and adrying time of 15 minutes.

After the fabrication process is finished, the total amount of enhancermixture in the dried adhesive polymer matrix is about 12-36% w/w of thepolymer matrix, more specifically between about 15 and 33%, yet morespecifically between about 18 and 30%, even more specifically betweenabout 21 and 27%, most specifically about 23-25% w/w, especially when anacrylate copolymer is used.

Post fabrication, the THDS of the invention also comprises specifiedamounts of individual skin permeation enhancers on a weight basis of theadhesive polymer matrix, which differ from the pre-drying amounts forthe reasons set forth above. Thus, in the dried adhesive polymer layer,DMSO comprises between about 4% and 12% by weight of the polymer matrix,more specifically between about 5% and 11%, yet more specifically about6-10%, even more specifically about 7-9%, and most specifically about 8%by weight of the adhesive polymer matrix. The fatty alcohol ester oflactic acid comprises between about 4.2% and 12.6% by weight of thepolymer matrix, more specifically between about 5.2% and 11.6%, yet morespecifically about 6.2-10.6%, even more specifically about 7.2-9.6%, andmost specifically about 8.4% by weight of the adhesive polymer matrix.The lower alkyl ester of lactic acid comprises between about 0.7% and2.3% by weight of the polymer matrix, more specifically between about1.0% and 2.0%, yet more specifically about 1.2-1.8%, and mostspecifically about 1.5% by weight of the adhesive polymer matrix. Thecapric acid comprises between about 3% and 9% by weight of the polymermatrix, more specifically between about 4% and 8%, yet more specificallyabout 5-7%, and most specifically about 6% by weight of the adhesivepolymer matrix.

Post-fabrication, it is also preferred that the skin permeationenhancers be present in the adhesive polymer matrix at a weight ratio asfollows: for each part of lower alkyl ester of lactic acid, about 4-8parts DMSO, about 4-8 parts fatty alcohol ester of lactic acid and about3-6 parts capric acid. Stated another way, the typical ratio is(4-8):(4-8):1:(3-6) of DMSO:fatty alcohol lactate ester:lower alkyllactate ester:capric acid. In preferred embodiments utilizing lauryllactate as the fatty alcohol lactate ester and ethyl lactate as thelower alkyl lactate ester, the weight ratio of DMSO to lauryl lactate isheld at between about 1:1.5 and 1.5:1, with an approximate 1:1 ratiobeing advantageous.

The dried adhesive polymer matrix is next laminated with a piece ofrelease liner (such as Scotchpak® 1022 or 9744, 3M Co., St. Paul Minn.)(or backing layer, if the alternative embodiment is utilized),preferably of the same size to form a sheet of the transdermal hormonedelivery systems. The resulting sheet can be cut to form discs orsquares and the like, with desired shapes and sizes using a steel ruledie and a hydraulic press. The discs or squares generally should notexceed about 60 cm² in area. Preferably, the discs or squares will beabout 5 to 50 cm², more preferably, about 8 to about 40 cm². Mostpreferably, the discs will be about 10 to about 20 cm². A disc of 15 cm²is preferred because of its relatively small size, yet being capable ofdispersing high levels of hormones. Specific embodiments of theinvention feature patches having a surface area of 10, 12.5, 15, 17.5 or20 cm². However, other sizes may be utilized. An advantage of the THDSof the present invention is that it can be fabricated with thin,translucent materials, such as the Scotchpak® 9732 backing layerexemplified herein. The small size and unobtrusive appearance of thepatch are cosmetically appealing to the user.

In a preferred embodiment of the invention, the THDS patches are adaptedwith an overlay film, which also may be selected from a variety of thin,preferably translucent films available in the art. In one embodiment,the overlay is designed to extend beyond the perimeter of the patch inall directions, typically by a margin of about 0.1 to 1.0 cm, morespecifically about 0.3 to 0.7 cm, and yet more specifically about 0.5 cmbeyond the perimeter of the patch. In an alternative embodiment, theoverlay is designed to extend partially beyond the edge of the patch,i.e., forming “tabs” of overlay material that extend beyond the edges ofthe patch. The overlay may be fabricated with the other elements of theTHDS, i.e., it may be affixed to the backing layer during fabrication ofthe THDS. Alternatively, the overlay may be fabricated separately, e.g.,with its own releasable liner, in a separate pouch, such that theoverlay may be applied at the discretion of the user. Overlay systemsare commonly utilized in patches and other dermal devices, and may beprepared according to any standard methodology.

Though patches without overlays are suitable for use in accordance withthe present invention, a patch comprising an overlay offers theadvantage of more secure adherence of the THDS for the duration of itsapplication (typically one week). Additionally, in a THDS without anoverlay, the perimeter of the patch can be tacky from the adhesivepolymer matrix, which extends to the very edge of the patch. The tackyperimeter can accumulate dirt, clothing lint and the like from theexternal environment, resulting in a cosmetically unappealing “darkring” appearance at the edge of the patch. In an overlay-style patch,the THDS perimeter is shielded from the external environment by theoverlay and the perimeter of the overlay exposes a much thinner edge tothe external environment (e.g., about 75-100 μm combined thickness ofoverlay film and adhesive in a preferred embodiment). This minimizes theaccumulation of external material onto the patch, and the “dark ring” issubstantially avoided—constituting another cosmetic advantage of theoverlay-style system.

The resulting THDS dosage units, prepared with or without overlay, arethen placed in appropriate packaging for storage, such as paper and/orfoil pouches, until they are to be applied in transdermal treatment.

Because of the importance of final absolute and relative amounts of skinpermeation enhancers in the THDS patches, if one or more of theforegoing formulation or process parameters is varied, an importantfinal step in the fabrication process is to quantitate these ingredientamounts after the process has been completed. This may be accomplishedaccording to standard analytical techniques well known in the art, e.g.,solvent extraction of components followed by liquid or gaschromatography. Examples of suitable methods are set forth in Example 2.

Methods of Use:

The THDS of the invention employs the general method of applying a patchto the skin of a subject for a pre-determined amount of timecommensurate with the particular condition being treated. The subject istypically a mammal and most typically a human, although the inventioncan be practiced on animals for various veterinary purposes. Typically,though this need not be the case, patches are formulated to deliver aneffective amount of one or more hormones to achieve the desired effect,for a period of between 1 and 7-9 days. For continual hormone delivery,the patch is replaced with a fresh patch before depletion of thehormone(s) therein below the effective amount. In a typical course ofongoing treatment, the patch is replaced once weekly.

Fertility control in women is a preferred use of the THDS of the presentinvention. For a contraceptive system employing a progestin and anestrogen, the THDS of the present invention provides an increased rateof hormone release, thereby providing a high rate of delivery of thehormones. The levels of levonorgestrel capable of being delivered by theTHDS of the invention exceed the level of about 1,000 pg/ml needed forcontraception. Indeed, levels of over 1500-2000 pg/ml are reached withthe system of the present invention (see Example 4). Further, the serumlevels of ethinyl estradiol range from about 20-80 pg/ml, therebyproviding effective support of the endometrium. Appropriate serum levelsof hormones may be obtained by using a relatively small patch asmentioned above, preferably 10 to 20 cm², specifically 10, 11, 12, 13,14, 15, 16, 17, 18, 19 or 20 (or intermediate increments, such as 12.5or 17.5 for example) cm² in area, which enhances the convenience to theuser.

Under certain conditions (e.g., other health conditions mandate againstestrogen use), fertility may be controlled using a progestin alone.Levonorgestrel is often preferred for use, but transdermal delivery ofsufficient amounts of levonorgestrel has been problematic heretofore.The THDS of the present invention is particularly advantageous in thisregard, given the high serum concentrations of levonorgestrel that canbe achieved through its use. For fertility control without estrogen, acontinuous serum level of 300 pg/ml has been found effective insubcutaneous levonorgestrel implants. This serum level is easilyachievable using the THDS of the invention.

Regimens for transdermal administration of hormones for control offertility are well known. Patches are usually formulated to deliverfertility-controlling amounts of the hormone(s) for a period of between1 and 7-9 days. In a typical regimen comprising a 28-day cycle, thepatch is replaced once weekly for three weeks. On the fourth week, nopatch is worn, or a placebo patch may be worn.

In an alternative regimen, a patch may be worn on the fourth week, thusproviding a continuous transdermal supply of the hormones. This regimenmay be utilized by women who wish to avoid menses entirely. It may becontinued indefinitely or terminated after a few months (e.g., 3, 4 or 6months).

The THDS of the invention may be utilized for indications other thanfertility control. For instance, estrogen/progestin combinations infertility-controlling amounts have also been utilized for control ofacne, control of symptoms of endometriosis and induction of amenorrhea.THDSs formulated with progestin (e.g., levonorgestrel) alone infertility-controlling amounts may also find utility to support pregnancyand for use in individuals for whom estrogen is contra-indicated (e.g.,women at risk of breast cancer), as well as for inhibition ofgalactorrhea, which is the secretion of breast milk in men ornon-breastfeeding women.

The THDS of the present invention offers many advantages overtransdermal hormone and contraceptive systems currently available. Asdiscussed in detail above, the primary advantage comprises delivery ofhigh amounts of fertility-controlling hormones, particularlylevonorgestrel, from a relatively small surface area patch, which may bemanufactured from backing and overlay materials that are thin andtranslucent, thereby increasing their cosmetic acceptability. Thesefeatures add to the utility and desirability of the THDS of theinvention for the multiple purposes described herein. Furthermore,breast tenderness and engorgement often associated with such therapieshave been found to be markedly reduced in patients using the THDS of thepresent invention, as compared with other systems, as has incidence ofnausea and/or vomiting.

The following examples are set forth to describe the invention ingreater detail. They are intended to illustrate, not to limit, theinvention.

Example 1 Fabrication of THDS Dosage Units for Use in Contraception

Materials: mg wt % Humectant PVP/VA-S630: 9.66 1.25 Skin permeationenhancers: DMSO 73.77 9.51 Lauryl lactate (Ceraphyl ® 31) 24.59 3.10Ethyl lactate 24.59 3.10 Capric Acid 18.54 2.39 Adhesive polymer: DuroTak 87-4098 617.59 79.65 Hormones: Levonorgestrel 4.48 0.58 Ethinylestradiol 2.20 0.28 Backing layer - Scotchpak ® 9732 (3M 16 sheets —Company) Release liner - Scotchpak ® 1022 (3M 16 sheets — Company) TOTAL775.41 mg 100.00%

Process:

Hormones were dissolved and dispersed in a solution comprising PVP/vinylacetate and the combination of skin permeation enhancers. Duro-Tak87-4098 (33% solid content) adhesive polymer solution was added, and thecontainer was sealed. The solution was stirred using a magnetic stirringbar at approximately 200 rpm at room temperature for 3 hours, to form ahomogeneous solution. The stirred solution was deaerated by allowing itto stand without stirring for one hour or until all air bubbles haddisappeared. The deaerated solution was coated onto a piece of thebacking layer to a thickness of 700 μm, then dried at 60° C. for 15minutes, using a laboratory coating/drying machine (Model LTSV/LTH,Werner Mathis, Switzerland). The dried adhesive polymer matrix waslaminated with a piece of release liner of the same size as the backinglayer, to form a sheet of THDS. The sheets were cut into dosage units of15 cm² using a steel rule die and hydraulic press at 4000 psi. Eachdosage unit was individually packaged in a paper or foil pouch andstored at 4° C.

Example 2 Quantitative Analysis of Dried Adhesive Polymer Matrix

The THDS dosage units fabricated as described in Example 1 weresubjected to quantitative analysis to determine the post-fabricationamounts of each component. Amounts of levonorgestrel (LNG) and ethinylestradiol (EE) were measured as follows. A dosage unit was taken fromits foil pouch and the release liner was removed. The dosage unit wasfolded together on the adhesive side and placed into an extractioncontainer, to which 100 ml of methanol was added. The container wasshaken vigorously by hand, then placed on an orbital shaker for at least12 hours, until all adhesive on the dosage units was dissolved.Twenty-one ml of the extracted solution was placed into a centrifugetube, and 9 ml of HPLC-grade water was added, to yield an aqueousmethanol solution composed of 70% methanol. The sample was centrifugedand the supernatant filtered through a 0.45 μm (nylon or Teflon) filterpaper into an HPLC vial. The filtrate was injected into a high pressureliquid chromatograph with UV monitor.

Amounts of other excipients were measured as follows. A dosage unit wastaken from its foil pouch and the release liner was removed. The dosageunit was folded together on the adhesive side cut into pieces and placedinto an extraction container, to which 2 ml of tetrahydrofuran (THF) wasadded to dissolve the adhesive. After four hours, 38 ml of hexanecontaining 0.01% (v/v) hexyl acetate (as an internal standard) was addedto the THF solution (volume ratio 5% THF). The container was shakenuntil the entire dosage unit was dissolved. The sample was centrifugedand was transferred into an HPLC vial. The filtrate was injected into agas chromatograph with FID detector. Results are shown below.

Average thickness of adhesive polymer matrix: 100 μm

Average composition of adhesive polymer matrix:

mg per 15 cm² Component: patch wt % PVP/VA-S630: 10.0 3.34 Duro Tak87-4098: 211.3 70.43 Enhancers: DMSO: 24.0 8.00 Lauryl lactate: 25.28.40 Ethyl lactate: 4.5 1.50 Capric Acid: 18.0 6.00 Hormones:Levonorgestrel 4.7 1.57 Ethinyl estradiol 2.3 0.77 TOTAL: 300.0 100.00

Example 3 Effects of Process Parameters on Final Composition of SkinPermeation Enhancers in the Adhesive Polymer Matrix

The effect of THDS fabrication parameters on the final composition ofskin permeation enhancers in the adhesive polymer matrix was tested.Four process parameters were varied: drying temperature, drying time,initial coating thickness and the weight percent of total enhancers inthe initial formulation. Results are shown in the table below. Eachvalue represents an average of four patches. Values are given in mg/g ofadhesive polymer matrix.

TABLE 1 Enhancer Composition in Patches Subjected to Varying ProcessParameters Drying Drying Coating Initial Temp. Time Thickness EnhancerEthyl Lauryl Grp # (° C.) (min) (mm) (Wt %) Lactate DMSO Capric AcidLactate 1 40 15 600 20.77 35.28 ± 1.17 224.84 ± 6.54  76.24 ± 1.12 99.78 ± 6.48 2 50 15 600 20.77 25.10 ± 0.74 158.04 ± 6.33  84.27 ± 2.56115.57 ± 3.84 3 60 15 600 20.77 17.74 ± 0.92 111.12 ± 3.19  90.07 ± 1.52124.79 ± 1.60 4 70 15 600 20.77 11.31 ± 0.78 53.32 ± 4.47 91.88 ± 4.17130.17 ± 4.27 5 80 15 600 20.77  7.55 ± 0.41 27.17 ± 4.23 92.87 ± 4.88138.30 ± 4.27 6 100 15 600 20.77  2.23 ± 0.21  2.00 ± 0.21 58.48 ± 1.72126.70 ± 2.97 7 60 5 600 20.77 37.52 ± 2.45 234.32 ± 7.67  74.14 ± 2.38108.28 ± 2.79 8 60 10 600 20.77 21.00 ± 0.46 154.11 ± 4.52  83.33 ± 2.23115.07 ± 3.55 3 60 15 600 20.77 17.74 ± 0.92 111.12 ± 3.19  90.07 ± 1.52124.79 ± 1.60 9 60 20 600 20.77 10.73 ± 0.55 74.64 ± 4.05 91.98 ± 1.76136.25 ± 2.68 10 60 25 600 20.77 ND 17.21 ± 1.16 107.94 ± 5.61  203.79 ±8.46 11 60 15 300 20.77  5.38 ± 0.61 47.51 ± 3.29 91.85 ± 1.73 135.87 ±4.09 12 60 15 400 20.77  5.07 ± 0.35 42.34 ± 4.51 92.77 ± 2.18 166.10 ±2.17 13 60 15 500 20.77  6.54 ± 0.27 76.17 ± 2.86 94.04 ± 5.31 154.79 ±9.54 3 60 15 600 20.77 17.74 ± 0.92 111.12 ± 3.19  90.07 ± 1.52 124.79 ±1.60 14 60 15 700 20.77 18.92 ± 1.06 137.58 ± 5.47  82.72 ± 3.64 120.69± 5.44 15 60 15 800 20.77 21.63 ± 0.42 142.27 ± 3.28  78.42 ± 1.19110.09 ± 1.12 16 60 15 600 7.15 ND ND  50.24 ± 10.64 ND 17 60 15 60011.98  7.64 ± 0.21 56.58 ± 1.37 60.23 ± 0.52  59.65 ± 1.36 18 60 15 60016.81 10.35 ± 1.37  76.71 ± 10.58  69.35 ± 12.03  94.64 ± 12.73 3 60 15600 20.77 17.74 ± 0.92 111.12 ± 3.19  90.07 ± 1.52 124.79 ± 1.60 19 6015 600 26.47 21.63 ± 0.42 142.27 ± 3.28  78.42 ± 1.19 110.09 ± 1.12 2080 5 600 20.77 13.35 ± 1.13 92.23 ± 7.15  68.15 ± 1.34 113.23 ± 4.28 2180 10 600 20.77  4.95 ± 0.41 40.69 ± 4.48 78.77 ± 1.98 110.59 ± 1.73 580 15 600 20.77  7.55 ± 0.41 27.17 ± 4.23 92.87 ± 4.88 138.30 ± 4.27 2280 20 600 20.77  0.29 ± 0.58  7.89 ± 1.35 67.02 ± 6.25 108.45 ± 6.55

Example 4 Clinical Study

An open-label, dose-response, 4-cycle, multi-center study was conductedto determine the levels LNG, EE, progesterone, LH and estradiol aftertreatment with a THDS produced according to the protocols set forth inExample 1. The objectives of the clinical study were: (1) to determinethe safety of a seven day LNG/EE THDS in healthy ovulatory women; (2) todetermine the serum levels of LNG and EE after treatment with an LNG/EETHDS; (3) to determine the serum levels of progesterone as an indicatorof ovulation after treatment with an LNG/EE THDS; and (4) to determinethe levels of LH and estradiol after treatment with an LNG/EE THDS.

The serum levels of LNG and EE were determined three times weeklythroughout the study. The serum levels of LH, estradiol, andprogesterone were also determined three times weekly throughout thestudy. Levels of progesterone equal to or greater than 3 ng/ml weretaken as presumptive evidence of ovulation. Cycle control was assessedby determining the incidence of spotting, breakthrough bleeding,withdrawal bleeding and amenorrhea from diary cards. Spotting wasdefined as a light flow that required the use of up to two sanitaryprotective pads. Breakthrough bleeding was defined as a heavier flowthat necessitated the use of three or more sanitary protection pads.Spotting and/or breakthrough bleeding was defined as any bleeding orspotting that occurred between days 5-21 except bleeding that beganprior to day 21 and continued past that date. Amenorrhea was defined asthe absence of any bleeding during the entire 28 day cycle. Withdrawalbleeding was defined as any spotting or bleeding of more than one day induration on or after day 22 (during the 7-day period in which no THDSwas applied.).

Safety was assessed by the adverse events that were described by thepatient without prompting. Changes in physical examinations, vitalsigns, and laboratory functions were also determined.

LNG serum samples were analyzed by RIA and EE serum samples wereanalyzed by gas chromatography/mass spectrometry to determine thesubjects' serum levels of those hormones periodically during the study.Preliminary results are shown in the table below, for patches of 15,17.5 and 20 cm², respectively, for the formula.

TABLE 2 Serum Levels of Levonorgestrel and Ethinyl Estradiol in ClinicalTrial Test Subjects During Four Cycles of Administration of THDSLevonorgestrel (pg/ml) Ethinyl Estradiol (pg/ml) Cycle Day 15 cm² 17.5cm² 20 cm² 15 cm² 17.5 cm² 20 cm² 1 1 2.00 2.00 2.00 1.08 ± 0.21 1.03 ±0.16 1.19 ± 0.41 (N = 11) (N = 11) (N = 17) (N = 10) (N = 11) (N = 17) 3 844.71 ± 724.50 1001.01 ± 634.24 920.73 ± 525.40 30.48 ± 9.56  41.77 ±21.88 42.73 ± 32.94 (N = 13) (N = 11) (N = 16) (N = 13) (N = 11) (N =16) 8 1054.45 ± 642.21 1249.42 ± 626.77 1019.48 ± 521.57  21.06 ± 6.50 32.78 ± 21.45 27.65 ± 24.10 (N = 11) (N = 12) (N = 18) (N = 11) (N = 12)(N = 19) 10 1589.84 ± 565.74  2052.75 ± 1100.75 2112.87 ± 693.04  30.88± 10.71 46.46 ± 23.52 39.79 ± 9.62  (N = 12) (N = 13) (N = 12) (N = 12)(N = 13) (N = 12) 15 1222.61 ± 399.92 1664.76 ± 462.71 1392.26 ± 711.44 24.35 ± 10.21 38.50 ± 18.62 23.19 ± 10.45 (N = 13) (N = 11) (N = 17) (N= 11) (N = 10) (N = 16) 17  2574.70 ± 1461.29  2644.92 ± 1506.96 2460.92± 1185.72 41.05 ± 13.17 60.78 ± 34.20 46.35 ± 23.74 (N = 12) (N = 9) (N= 14) (N = 11) (N = 10) (N = 16) 22 1460.10 ± 574.76 1898.69 ± 843.731616.14 ± 1033.81 22.27 ± 9.82  41.54 ± 18.81 29.73 ± 23.84 (N = 12) (N= 12) (N = 17) (N = 12) (N = 13) (N = 19) 2 1  923.77 ± 1184.97  408.51± 683.41 254.44 ± 418.96 18.46 ± 18.42 9.25 ± 8.19 11.89 ± 17.09 (N = 7)(N = 8) (N = 8) (N = 7) (N = 8) (N = 8) 3 1223.70 ± 277.64  1820.44 ±1084.88 1513.82 ± 601.49  35.51 ± 14.05 64.65 ± 25.22 39.70 ± 15.82 (N =5) (N = 9) (N = 7) (N = 6) (N = 8) (N = 7) 8  929.07 ± 126.26 1442.98 ±689.62 1397.46 ± 815.37  28.44 ± 16.11 40.24 ± 19.43 36.19 ± 23.06 (N =6) (N = 9) (N = 7) (N = 7) (N = 9) (N = 7) 10 1904.12 ± 583.88  2433.64± 1092.91 3016.86 ± 1871.56 36.49 ± 13.86 58.67 ± 33.72 49.12 ± 22.02 (N= 6) (N = 9) (N = 7) (N = 6) (N = 9) (N = 7) 15 1454.02 ± 597.78 1545.99± 639.46 1940.63 ± 1118.38 26.90 ± 9.54 39.57 ± 22.80 25.15 ± 8.81  (N =7) (N = 9) (N = 6) (N = 7) (N = 9) (N = 6) 17  2674.99 ± 1335.90 3177.80 ± 1379.79 2863.36 ± 1556.44 40.23 ± 14.93 65.79 ± 33.65 41.82 ±17.90 (N = 7) (N = 7) (N = 7) (N = 7) (N = 7) (N = 7) 22 1403.37 ±413.89 1811.11 ± 856.59 2071.22 ± 1161.46 27.32 ± 18.59 36.49 ± 21.3826.11 ± 13.85 (N = 7) (N = 9) (N = 7) (N = 7) (N = 9) (N = 6) 3 1 62.002.00 97.38 ± 66.64 5.63 0.98 5.92 ± 3.52 (N = 4) (N = 4) 3 467.002124.11 1878.00 ± 506.67  19.38 80.24 43.15 ± 15.74 (N = 4) (N = 4) 8 362.41 ± 164.88 1424.82 2026.13 ± 943.19  18.89 ± 20.14 31.98 33.37 ±13.09 (N = 2) (N = 4) (N = 2) (N = 4) 10 1084.63 ± 266.77 3274.463780.44 ± 1783.33 41.77 ± 15.76 101.75 52.07 ± 12.37 (N = 2) (N = 4) (N= 2) (N = 4) 15  937.32 ± 176.32 1775.66 2500.13 ± 752.94  34.20 ± 17.4243.61 27.72 ± 6.83  (N = 2) (N = 4) (N = 2) (N = 4) 17  947.81 ± 978.377175.00 2911.94 ± 953.73  31.06 ± 34.20 87.21 25.34 ± 10.93 (N = 2) (N =4) (N = 2) (N = 4) 22  919.69 ± 116.95 2274.46 2175.81 ± 1273.49 22.17 ±4.83 34.89 29.20 ± 12.24 (N = 2) (N = 4) (N = 2) (N = 4) 4 1 49.00 ND44.13 ± 59.57 4.38 ND 3.30 ± 3.29 (N = 2) (N = 2) 8 576.00 ND 1559.75 ±392.09 16.88 ND 34.51 (N = 2) 15 940.00 ND 2634.88 ± 1458.23 10.63 ND27.16 ± 4.91 (N = 2) (N = 2) 22 1283.00 2588.50 ± 1093.89 17.50 ND 23.01± 3.70 (N = 2) (N = 2)

The present invention is not limited to the embodiments described andexemplified above, but is capable of variation and modification withinthe scope of the appended claims.

What is claimed:
 1. A method of controlling fertility in a female,comprising applying to the skin of the female a transdermal hormonedelivery device comprising a backing layer and an adhesive polymermatrix affixed to the backing layer, the adhesive polymer matrixcomprising levonorgestrel and ethinyl estradiol, wherein application ofthe device to the skin of a female for one or more one-week dosingperiods results in an in vivo serum concentration profile oflevonorgestrel in which a maximum concentration is reached by or beforeabout midway through the dosing period and thereafter declines to theend of the dosing period, and an average serum concentration of at leastabout 1,000 pg/ml levonorgestrel is achieved for the dosing period,wherein the device is applied to the skin in a four-week regimencomprising application of one device once each week for threeconsecutive weeks, followed by one week in which the device optionallyis not applied, thereby controlling fertility in the female.
 2. Themethod of claim 1, wherein the C_(max) of levonorgestrel during a dosingperiod is up to about 4,500 pg/ml.
 3. The method of claim 1, wherein theaverage AUC for levonorgestrel for three consecutive dosing periods isbetween about 18,390+/−1,603 pg-day/ml and about 59,036+/−6,163pg-day/ml.
 4. The method of claim 1, wherein the average serumconcentration of levonorgestrel per dosing period increases from week toweek in the three consecutive weeks of the four week dosing regimen. 5.The method of claim 1, wherein the application of the device to the skinof the female for the one or more one-week dosing periods results in anin vivo serum concentration profile of ethinyl estradiol in which amaximum concentration is reached by or before about midway through thedosing period and thereafter declines to the end of the dosing period.6. The method of claim 5, wherein an average serum concentration of notmore than about 64+/−4 pg/ml ethinyl estradiol is achieved for thedosing period.
 7. The method of claim 5, wherein the C_(max) of ethinylestradiol during the dosing period is up to about 90 pg/ml.
 8. Themethod of claim 5, wherein the average AUC for ethinyl estradiol forthree consecutive dosing periods is no more than about 1,456+/−101pg-day/ml.